APRIL is expressed as a type-II transmembrane protein, but unlike most other TNF family members it is mainly processed as a secreted protein and cleaved in the Golgi apparatus where it is cleaved by a furin convertase to release a soluble active form (Lopez-Fraga et al., 2001, EMBO Rep 2, 945-51,). APRIL assembles as a non-covalently linked homo-trimer with similar structural homology in protein fold to a number of other TNF family ligands (Wallweber et al., 2004, Mol Biol 343, 283-90). APRIL binds two TNF receptors: B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). In addition, APRIL has recently been shown to bind heparan sulphate proteoglycans (HSPGs) (Hendriks et al., 2005, Cell Death Differ 12, 637-48).
APRIL shows high homology (30%) to another member of the TNF superfamily, B cell activating factor belonging to the TNF family (BAFF or B Lymphocyte stimulator, BLyS), with which it shares binding to its receptors, BCMA and TACI. BAFF is also known to bind a unique receptor, BAFF-Receptor, and through this mediates crucial survival signals during B cell development (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). APRIL and BAFF have been suggested to form mixed trimers (Roschke et al., 2002, J Immunol. 169(8):4314-21). Such mixed trimers were found to occur at a higher prevalence in rheumatoid arthritis (RA) patients.
APRIL is predominantly expressed by immune cell subsets such as monocytes, macrophages, dendritic cells, neutrophils, B-cells, and T-cells, many of which also express BAFF. In addition, APRIL can be expressed by non-immune cells such as osteoclasts, epithelial cells and a variety of tumour tissues (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8).
The function of APRIL was established using mouse genetic models. hAPRIL transgenic mice develop normally, but showed enhanced T cell survival and elevated levels of IgM antibodies (Stein et al., 2002, J Clin Invest 109, 1587-98). In addition, T cell independent type II responses were enhanced. Aged hAPRIL transgenic mice displayed extreme enlargement and re-organisation of the lymph system and enlarged spleen due to infiltration of CD5 positive B cells, a phenotype closely resembling human B-CLL (Planelles et al., 2004, Cancer Cell 6, 399-408). APRIL deficient mice were found to have decreased levels of IgA in circulation and upon challenge with a T-cell dependent antigen (Castigli et al., 2004, Proc Natl Acad Sci USA 101, 3903-8; Varfolomeev et al., 2004, Mol Cell Biol 24, 997-1006). Next, APRIL, along with BAFF, was demonstrated to function in class-switch recombination (CSR) of antibodies to both IgG and IgA, independently of CD40-CD40L signaling (Litinskiy et al., 2002, Nat Immunol 3, 822-9). In addition, APRIL was demonstrated to be less critical than BAFF in B cell maintenance, but was shown to have a role in B cell signalling and drive both proliferation and survival of human and murine B cells in-vitro (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8).
APRIL was originally identified based on its expression in cancer cells (Hahne et al., 1998, J Exp Med 188, 1185-90). High expression levels of APRIL mRNA were found in a panel of tumour cell lines as well as human primary tumours such as colon, and a lymphoid carcinoma. In addition, APRIL transfected murine fibroblast NIH-3T3 cells were shown to grow more rapidly in immunodeficient mice. More importantly, blocking APRIL using a soluble APRIL receptor was shown to inhibit tumour growth of lung and colon carcinomas (Rennert et al., 2000, J Exp Med 192, 1677-84).
Chronic Lymphocytic Leukaemia (CLL) B cells express both APRIL and APRIL-receptors. In addition, it was shown that APRIL protected CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-κB activation (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). A retrospective study under 95 CLL patients showed increased levels of APRIL in serum, which correlated with disease progression and overall patient survival, with a poorer prognosis for patients with high APRIL serum levels (Planelles et al., 2007, Haematologica 92, 1284-5).
Similarly, (increased levels of) APRIL was shown to be expressed in Hodgkin's lymphoma, Non-Hodgkin's lymphoma (NHL) and Multiple Myeloma (MM) (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). A retrospective study in DLBCL patients (NHL) showed that high APRIL expression in cancer lesions correlated with a poor survival rate (Schwaller et al., 2007, Blood 109, 331-8). Using NHL and MM cell-lines it was shown that treatment with APRIL or BAFF increased survival via NF-κB activation and up-regulation of pro-survival proteins (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8). In accordance with this pro-survival role of APRIL, MM cells were shown to undergo apoptosis when cultured in the presence of TACI-Fc. Since BAFF-receptor was less effective in enhancing apoptosis, this indicates that APRIL, and not BAFF is primarily responsible for enhanced survival in these cells (Abe et al., 2006, Leukemia 20, 1313-5).
APRIL was also found to be over-expressed in a number of cell lines derived from solid tumours. Indeed, APRIL was able to stimulate in-vitro proliferation of a number of these cell lines (reviewed in Kimberley et al., 2009, J Cell Physiol. 218(1):1-8).
Due to its role in B cell biology APRIL also plays a role in many autoimmune diseases. Indeed, atacicept (a commercial TACI-Fc preparation) is already in numerous clinical trials for treatment of several autoimmune diseases (reviewed in Gatto et al., 2008, Curr Opin Investig Drugs. 9(11):1216-27). Increased serum levels of APRIL and BAFF have been reported in many SLE patients (Koyama et al., 2005, Ann Rheum Dis 64, 1065-7). A retrospective analysis revealed that APRIL serum levels tended to correlate with anti-dsDNA antibody titres. Evidence that APRIL may play a functional role in SLE was obtained by testing the effect of TACI-Fc fusion protein into lupus prone mice (Gross et al., 2000, Nature 404, 995-9), which prevented disease development and prolonged survival.
In addition, inhibition of APRIL and BAFF with TACI-Fc in the CIA mouse model of rheumatoid arthritis was also found to prevent disease progression and lower disease scores, compared with controls (Gross et al., 2001, Immunity 15, 289-302; Wang et al., 2001, Nat Immunol 2, 632-7). Also in another arthritis model, synovium-SCID mouse chimeras, TACI-Fc showed a beneficial effect (Seyler et al., 2005, J Clin Invest 115, 3083-92). Treatment with TACI-Fc resulted in the disappearance of Germinal Centers in the synovial tissue, decreased Ig production and decreased production of IFN-gamma.
It was later reported that the synovial fluid of patients with inflammatory arthritis had significantly increased APRIL levels compared with those with patients suffering from non-inflammatory arthritis such as osteoarthritis (Stohl et al., 2006, Endocr Metab Immune Disord Drug Targets 6, 351-8; Tan et al., 2003, Arthritis Rheum 48, 982-92).
Several studies focused on the presence of APRIL in the sera of patients suffering from a wider range of systemic immune-based rheumatic diseases (now also including Sjögren's syndrome, Reiter's syndrome, psoriatic arthritis, polymyositis, and ankylosing spondylitis) and found significantly increased APRIL levels in these patients, suggesting an important role for APRIL in these diseases as well (Jonsson et al., 1986, Scand J Rheumatol Suppl 61, 166-9; Roschke et al., 2002, J Immunol 169, 4314-21).
Finally, increased APRIL expression has also been linked to Multiple Sclerosis (MS). APRIL expression was found to be increased in the astrocytes of MS sufferers compared with normal controls. This is in line with the described APRIL expression in glioblastomas and in the serum of glioblastoma patients (Deshayes et al., 2004, Oncogene 23, 3005-12; Roth et al., 2001, Cell Death Differ 8, 403-10).